Emerging stem cell-based tissue engineering therapies that provide a biological solution to cartilage degeneration are considered advantageous over existing pharmacological or surgical approaches. While mesenchymal stem cells (MSCs) deriving from adult tissues such as bone marrow (BM) or fat are the most commonly used stem cell type in studies to date, the cells have several inherent properties that limit their potential for use in cartilage tissue engineering. We have recently demonstrated that cell reprogramming technology is able to transform a patient's own peripheral blood mononuclear cells into induced pluripotent stem cells (iPSCs) as a robust MSC source for tissue engineering. The use of iPSC-derived MSCs provides an opportunity for the development of personalized medicine for disease treatment. The objective of this proposed study is to develop an effective tissue engineering therapy for treatment of cartilage lesions caused by injuries or diseases, such as osteoarthritis (OA). We will explore the potential of using iPSC-derived MSCs to generate engineered cartilage in vitro and implanting the engineered cartilage for cartilage repair in vivo. To achieve the aim, we propose to establish working iPSC-derived MSC lines by reprogramming peripheral blood mononuclear cells harvested from human OA patients or sheep into iPSCs, and then deriving MSCs from the iPSCs. We will then culture iPSC-derived MSCs in functional nanofibrous scaffolds capable of preserving and releasing chondrogenic growth factors in a controllable fashion to generate cartilage. Cartilage generated from autologous sheep iPSC- or BM-derived MSCs, or xenogeneic human iPSC- derived MSCs will be used to repair cartilage in a sheep model. Comparison of these different groups with acellular scaffolds or a clinically relevant cartilage repair control, microfracture, will demonstrate the capability o different stem cell-based, engineered cartilage implants for the repair of cartilage defects. This project is innovative because we will apply transgene-free iPSC, nanofiber, controlled release and bioreactor technologies to enhance MSC chondrogenesis, and cartilage generation and repair in a large animal model to demonstrate the potential of our unique approach for clinical translation.